PT  - JOURNAL ARTICLE
AU  - Esfahani A Hadizadeh
AU  - A Sverchkova
AU  - J Saez-Rodriguez
AU  - AA Schuppert
AU  - M Brehme
TI  - A Systematic Atlas of Chaperome Deregulation Topologies Across the Human Cancer Landscape
AID  - 10.1101/122044
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 122044
4099  - http://biorxiv.org/content/early/2017/03/29/122044.short
4100  - http://biorxiv.org/content/early/2017/03/29/122044.full
AB  - Proteome balance is safeguarded by the proteostasis network (PN), an intricately regulated network of conserved processes that have evolved to maintain native function of the diverse ensemble of protein species, ensuring cellular and organismal health. Proteostasis imbalances and collapse are increasingly implicated in a spectrum of human diseases, from neurodegeneration to cancer. The pattern and extent of PN disease alterations however have not been assessed in a systematic and quantitative way at a systems level. Zooming in on the chaperome as a central PN component we turned to a curated functional ontology of the human chaperome that we connect in a high-confidence physical protein-protein interactome network. Challenged by the lack of a systems-level understanding of proteostasis alterations in the heterogeneous spectrum of human cancers, we assessed gene expression across more than 10,000 human patient biopsies covering 22 solid cancers and found the chaperome consistently highly upregulated. Increased levels of several chaperones such as HSP90 have previously been associated with poor prognosis in cancers. We used a customized Meta-PCA dimension reduction approach to condense the complexity of cancer transcriptomics datasets into an atlas of quantitative topographic maps. We confirm consist upregulation of the HSP90 family and also highlight HSP60s, Prefoldins, HSP100s, and mitochondria-specific chaperones as pan-cancer enriched. Our analysis also reveals a surprisingly consistent downregulation of small heat shock proteins (sHSPs). Strikingly, this analysis also highlights similarities between stem cell and cancer proteostasis, and diametrically opposed chaperome deregulation between cancers and neurodegenerative diseases. We developed a web-based Proteostasis Profiler tool (Pro2) enabling analysis and intuitive visual exploration of proteostasis disease alterations using gene expression data. Our study showcases a comprehensive profiling of chaperome network shifts in human cancers and sets the stage for a systematic global analysis of PN alterations across the human diseasome towards novel hypotheses for therapeutic network re-adjustment in proteostasis disorders.